The fact that psychologic stress can precipitate or alter the course of organic diseases has long been recognized. An essential challenge in psychosomatic-psychobiological research is to delineate the mechanisms by which experience causes certain types of physiological reactions that result in disease states. In addition, the mechanisms of neurobiological modulating systems need to be understood at the molecular and genetic levels. Recent and ongoing developments in cellular and molecular biology provide some research models by which transducing mechanisms involved in psychosomatic reactions can be understood at the most fundamental level. It has been suggested that anxiety can occur as a result of acquired neurophysiological chemosensitivity. Stimuli that produce "chronic anxiety" in the sea snail aplysia cause the enhancement of connections made by the sensory neurons on their target cells--that is, interneurons and motor neurons. The enhancing process, deemed postsynaptic facilitation, is caused by noxious stimuli that activate cells that use a serotonin-like neurotransmitter. Those cells on the head of the aplysia act as a defensive arousal system, impinge on the synaptic terminals of the reflex system for gill withdrawal, and enhance the connections that the sensory synapses make on the motor neurons and interneurons. Serotonin appears to play a major role in the defensive arousal process by increasing intracellular cAMP, which then strengthens the neuroconnectors of the sensory neurons by facilitating neurotransmitter release. In accordance with the present invention, substance P has been found to play an important role in the inducement of disease states by psychobiological reactions.
With respect to psychoimmunologic disorders, interest in the interactions between the central nervous system and the immune system date back to Aristotle, who hypothesized a connection between physical health and mood. Later, Sir William Osler spoke of the importance of knowing what is going on in a patient's head, as well as the lungs, in predicting the outcome of pulmonary tuberculosis. During the mid 1950s Selye demonstrated a clear relation among brain activity, endocrine organs, and immune function. In 1964 the field was first referred to as psychoimmunology, later amended to psychoneuroimmunology, the study of the interaction of consciousness, the brain and the central nervous system, and the body's immune system. In recent years major advances have been made in establishing direct evidence for a brain-immune system relation. In serving functions of adaptation and defense, both the central nervous system and the immune system discriminate between self and nonself, and they incorporate principles of recognition, learning, memory, and transmission of information. Evidence for such a communication system ranges from anatomical confirmation of the central nervous system innervation of immune organs to reports documenting the behavioral effects on immune response and tumor acquisition in experimental animals. A number of studies involving experimental animals and human autopsy specimens have shown direct sympathetic nervous system innervation of the spleen, the thymus, and the lymph nodes. Cholinergic innervation of the thymus gland has now been documented, and investigators have described noradrenergic innervation of lymphoid tissue in a variety of mammalian species, including humans.
Lending further evidence is the presence of receptors for various neurotransmitters, neurohormones, and neuropeptides on cells of the immune system. In particular, neurokinin receptors have been found in lymphatic tissue. Noradrenergic receptors have been found on lymphocytes that appear to be exclusively for beta2-adrenergic receptors, which are similar to those found in the smooth muscles of the bronchi and the lungs. In addition to the noradrenergic receptors of the beta-1 subtype, evidence indicates the presence on lymphocytes of receptors for gonadal steroids, endorphins, enkephalins, corticotropin, vasointestinal peptide, cholecystokinin, neurotensin, acetylcholine, and serotonin. Recent evidence also indicates that lymphocytes may synthesize some neurohormones de novo.
Although some studies suggest that bereavement and depression can interfere with immunological competence, the findings in this area of research have been diverse and often inconsistent. Studies of bereaved men and women have reported reduced in vitro lymphocyte response to mitogen stimulation, with normal levels of circulating immunoglobulins and normal responses on delayed hypersensitivity skin tests; the reduced lymphocyte response is most dramatic in bereaved patients with depressive symptoms. A recent meta-analysis of methodologically sound studies addressing cellular immunity in depression found that the immune abnormalities reliably associated with depression were (1) decreased proliferative response of lymphocytes to mitogen stimulation, (2) decreased natural killer cell activity, and (3) abnormalities of different white blood cell lines. The magnitude of these immune system abnormalities correlated with the intensity of depressed mood. However, methodological concerns limit the interpretation and generalizability of much of the available data on the immune system in depression; there is a high incidence of failure to replicate findings.
Although the present invention is not limited to a specific mechanism of action, the inventors postulate that a potential explanation for some of the diverse findings may involve high catecholamine output and the increased production of prostaglandins, each of which has been observed separately in studies of depressed patients. Catecholamines, acting through beta-adrenergic receptors, are known to suppress the activity of human natural killer cells. Prostaglandins, functioning through a complex interaction between second messenger systems, may inhibit in vitro mitogen-induced lymphocyte proliferation. Because recent animal work suggests that prostaglandin production is increased by catecholamines through a nonreceptor-mediated mechanism, the diminished immunological competence reported in depressed patients may be a result of the dysregulation of the catecholaminergic system. In accordance with the present invention, the neuropeptide substance P is postulated to play in important role in this mechanism. Accordingly, a tacykinin antagonist, in particular a neurokinin-1 receptor antagonist would be useful in the treatment or prevention of a psychosomatic disorder or a psychoimmunologic disorder.
Antidepressant and antianxiety agents have been employed for psychosomatic or psychoimmunologic disorders with limited success. In addition, certain side effects may be present with such treatment. These approaches have had limited success, however, and an alternate means of treating or preventing psychosomatic or psychoimmunologic disorders would be of great benefit.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42, 1295-1305 (1988)).
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1, neurokinin-2, and neurokinin-3, respectively.
Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)).
Neurokinin-1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, PCT Patent Publication Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, PCT Patent Publication No. WO 96/24353 suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). However, such as regimen would not be free of side-effects due to the serotonin agonist or SSRI. Currently there are only limited means for treating or preventing psychosomatic or psychoimmunologic disorders. In view of the short-comings of existing agents, there is a need for new effective methods for treating or preventing psychosomatic and psychoimmunologic disorders.